4-(Pyrrolidinyl)methoxybenzoic Acid Derivatives as a Potent, Orally Active VLA-4 Antagonist

A novel series of benzoic acid derivatives as VLA-4 antagonists were synthesized. Optimization, focusing on activity and lipophilicity needed for cell permeability, resulted in the identification of 15b and 15e with good activity (IC50=1.6 nM each) and moderate lipophilicity (Log D=2.0, 1.8). Furthe...

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Veröffentlicht in:	Chemical & Pharmaceutical Bulletin 2006, Vol.54(11), pp.1515-1529
Hauptverfasser:	Chiba, Jun, Iimura, Shin, Yoneda, Yoshiyuki, Sugimoto, Yuichi, Horiuchi, Takao, Muro, Fumito, Ochiai, Yuichi, Ogasawara, Tomomi, Tsubokawa, Masao, Iigou, Yutaka, Takayama, Gensuke, Taira, Tomoe, Takata, Yoshimi, Yokoyama, Mika, Takashi, Tohru, Nakayama, Atsushi, Machinaga, Nobuo
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Animals asthma Asthma - drug therapy Benzoates - administration & dosage Benzoates - chemistry Benzoates - pharmacokinetics Cell Membrane Permeability - drug effects Disease Models, Animal Dogs Drug Evaluation, Preclinical Enzyme Activation - drug effects human serum albumin Hydroxybenzoate Ethers integrin Integrin alpha4beta1 - antagonists & inhibitors Kidney - cytology Male Mice Mice, Inbred BALB C Molecular Conformation Pyrrolidines - chemistry Pyrrolidinones - administration & dosage Pyrrolidinones - chemistry Pyrrolidinones - pharmacokinetics Rats Rats, Sprague-Dawley Stereoisomerism Structure-Activity Relationship VLA-4
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Zusammenfassung:	A novel series of benzoic acid derivatives as VLA-4 antagonists were synthesized. Optimization, focusing on activity and lipophilicity needed for cell permeability, resulted in the identification of 15b and 15e with good activity (IC50=1.6 nM each) and moderate lipophilicity (Log D=2.0, 1.8). Furthermore, 15e demonstrated efficacy in murine asthma model by an oral dose of 30 mg/kg.
ISSN:	0009-2363 1347-5223
DOI:	10.1248/cpb.54.1515